tbuckley/cabot-search huggingface dataset:
DIPG-27. DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) CHALLENGE: FROM GENE EXPRESSION PROFILE TO DRUG
Authors: Antonio Scilimati, Domenico Armenise, Olga Baldelli, Antonella Centonze, Davide Derri, Savina Ferorelli, Morena Miciaccia, Roberta Solidoro, Maria Grazia Perrone
Journal: Neuro-Oncology (2023)

Abstract Diffuse intrinsic pontine glioma (DIPG) accounts for 80% of pediatric brainstem tumors and about 10-20% of all central nervous system tumors in childhood. Despite the adoption of aggressive therapeutic approaches, DIPG remains the leading cause of cancer-related mortality in childhood: prognosis is still poor with more than 90% of affected children dying within 18-24 months from the diagnosis.1 Decades of clinical attempts involving more than 200 trials evaluating different conventional cytotoxic drugs, targeted drugs and studies with radiation dose escalating and new radio sensitizing agents, have failed to improve the overall survival of children with DIPG. Since available drugs have proven no benefits hereto for DIPG, it is fundamental to gain insights into the gene expression profile of DIPG patients and speed up the discovery of novel therapeutics for this dismal malignancy. Only the compound ONC201 was discovered to reduce DIPG tumors size in DIPG H3K27M mutated and now is in phase III clinical trials. Given the complex molecular mechanisms underlying DIPG, it would be necessary to fully utilize gene expression profiles to build a fully knowledge of DIPG-related genes and pathways. Preliminarily, the gene expression profile of eight pediatric DIPG samples and two primary pontine tissue samples was downloaded and analyzed starting from the Gene Expression Omnibus (GEO) database2. The GEO data were used to evaluate the differentially expressed genes (DEGs) in the pediatric DIPG samples. Subsequently, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and Reactome pathways of DEGs were enriched, integrated, and analyzed to find out genes and signaling pathways involved in the biological and clinic-pathological features of DIPG. More data are being to be added to our meta-analysis.
Retraction Notice to: Coordinated Silencing of MYC-Mediated miR-29 by HDAC3 and EZH2 as a Therapeutic Target of Histone Modification in Aggressive B-Cell Lymphomas
Authors: Xinwei Zhang, Xiaohong Zhao, Warren Fiskus, Jianhong Lin, Tint Lwin, Rekha Rao, Yizhuo Zhang, John C. Chan, Kai Fu, Victor E. Marquez, Selina Chen-Kiang, Lynn C. Moscinski, Edward Seto, William S. Dalton, Kenneth L. Wright, Eduardo Sotomayor, Kapil Bhalla, Jianguo Tao
Journal: Cancer Cell (2023)
Genome-wide association study of thoracic aortic aneurysm and dissection in the Million Veteran Program
Authors: Derek Klarin, Poornima Devineni, Anoop K. Sendamarai, Anthony R. Angueira, Sarah E. Graham, Ying H. Shen, Michael G. Levin, James P. Pirruccello, Ida Surakka, Purushotham R. Karnam, Tanmoy Roychowdhury, Yanming Li, Minxian Wang, Krishna G. Aragam, Kaavya Paruchuri, Verena Zuber, Gabrielle E. Shakt, Noah L. Tsao, Renae L. Judy, Ha My T. Vy, Shefali S. Verma, Daniel J. Rader, Ron Do, Joseph E. Bavaria, Girish N. Nadkarni, Marylyn D. Ritchie, Stephen Burgess, Dong-chuan Guo, Patrick T. Ellinor, Scott A. LeMaire, Dianna M. Milewicz, Cristen J. Willer, Pradeep Natarajan, Philip S. Tsao, Saiju Pyarajan, Scott M. Damrauer
Journal: Nature Genetics (2023)

Abstract The current understanding of the genetic determinants of thoracic aortic aneurysms and dissections (TAAD) has largely been informed through studies of rare, Mendelian forms of disease. Here, we conducted a genome-wide association study (GWAS) of TAAD, testing ~25 million DNA sequence variants in 8,626 participants with and 453,043 participants without TAAD in the Million Veteran Program, with replication in an independent sample of 4,459 individuals with and 512,463 without TAAD from six cohorts. We identified 21 TAAD risk loci, 17 of which have not been previously reported. We leverage multiple downstream analytic methods to identify causal TAAD risk genes and cell types and provide human genetic evidence that TAAD is a non-atherosclerotic aortic disorder distinct from other forms of vascular disease. Our results demonstrate that the genetic architecture of TAAD mirrors that of other complex traits and that it is not solely inherited through protein-altering variants of large effect size.
LGG-24. DIFFUSE LEPTOMENINGEAL GLIONEURONAL TUMOR MANAGEMENT AND OUTCOME: A SINGLE CENTER EXPERIENCE
Authors: Faryal Munir, Jiasen He, Irtiza Sheikh, Melissa Chen, Jason Johnson, Mary McAleer, Susan McGovern, Arnold Paulino, Jason Huse, David Sandberg, Wafik Zaky
Journal: Neuro-Oncology (2023)

Abstract Diffuse leptomeningeal glioneuronal tumor (DLGNT) is a rare diagnosis that was first incorporated into the WHO Classification in 2016. DLGNTs are usually low-grade tumors, with no current standard of care. A retrospective review of patients with a histologic diagnosis of DLGNT, from 2010 to 2022, was done with IRB approval. Eight patients were identified with a median age at diagnosis of 5.5 years (range 4 months - 21 years). Imaging findings included diffuse leptomeningeal enhancement and multifocal nodular lesions in the supratentorial and infratentorial locations. One patient had localized pineal disease and 2 patients had isolated spinal cord involvement. Histologically, 6/8 (75%) patients showed low-grade tumor (Ki-67 index = 2-15%). BRAF-KIAA1549 fusion was reported in 3, NTRK fusion in 1, PTPN11 mutation in 1, and FGFR1 mutation in 1 patient. Seven patients (88%) were treated with proton radiation, 3 at diagnosis and 4 upon progression. Chemotherapy was used at diagnosis on 4 patients (temozolomide, carboplatin and vincristine, and vinblastine). Targeted therapy (NTRK or BRAF-inhibitors) was utilized upon progression in four patients, and at diagnosis in one. All patients showed disease progression at a median time of 24 months from diagnosis. The median progression-free survival (PFS) in the group receiving upfront RT was 2.2 years (range = 0.4 – 6.6 years), versus chemotherapy of 1.4 years (range = 0.15 - 2.6 years) The 2 years PFS and OS are 57% and 100%, respectively. At a median follow-up of 4.5 years (range = 3 months to 9 years), 6 patients have stable disease (of whom 2 are off therapy), and 2 patients have progressive disease. DLGNTs are rare tumors with scarce data about radiological and molecular characteristics, and no established standard of care. Our case series emphasizes the need for further studies on molecular profiling and exploring targeted therapies.
BIOL-19. DIFFUSE MIDLINE GLIOMA CEREBRAL ORGANOID MODEL AND MULTIOMICS CHARACTERIZATION
Authors: Sudarshawn Damodharan, Peter Favreau, Connie Lebakken, Mahua Dey
Journal: Neuro-Oncology (2023)

Abstract Diffuse midline glioma (DMG) are highly aggressive malignancies of the central nervous system that primarily affect the pediatric population. These tumors are historically universally fatal with no curative treatment options available. There is a need to identify more targeted and optimal treatments for these patients. Current approaches to pre-clinical therapeutic testing have been limited by many obstacles to effectively translate theses to patients. It is known that the interactions between tumors and the other components of the tumor microenvironment (TME) can change the response to therapeutic interventions. This especially holds true for brain tumors and the complex neural network encompassed within their TME. Given this, it is crucial to develop more realistic DMG models that integrate this to conduct therapeutic testing rather than relying upon conventional cell culture models. The goal of our study was to develop a three-dimensional DMG cerebral organoid model derived from human induced pluripotent stem cells (iPSCs) co-cultured with three different DMG patient-derived xenograft (PDX) cell lines to better mimic the TME for therapeutic testing. We were able to successfully integrate our three cell lines into the cerebral organoids, capturing TME interactions along with performing multiomic profiling for better characterization. We next plan to perform therapeutic testing to further validate the model and improve preclinical drug screening for DMG.
RARE-06. DISSECTING CELLULAR DIFFERENTIATION HETEROGENEITY IN CHOROID PLEXUS CARCINOMA PATHOGENESIS
Authors: Lukas Faltings, Noreen Mian, Anjali Siluveru, Siddhi Modi, James Virga, Ping Cao, Haotian Zhao
Journal: Neuro-Oncology (2023)

Abstract Choroid plexus (CP) neoplasms are rare, predominantly pediatric, brain tumors ranging from benign CP papilloma to aggressive CP carcinoma (CPC) associated with poor survival. Survivors often experience devastating side effects from current treatment strategies. There is an urgent need for safer, more effective therapies for CPC. A subset of human CPC exhibits abnormal NOTCH activity, whereas mutations of tumor suppressor gene TP53 are detected in &amp;gt;50% of CPC and are associated with increased genetic tumor instability and worse prognosis. CPC is one hallmark of Li-Fraumeni syndrome (LFS), a rare genetic disorder associated with germline TP53 mutations. Human CP tumors also frequently display aberrant expression of transcriptional regulators of roof plate/CP differentiation, including LIM homeodomain transcription factors LMX1A, and SRY-Box Transcription Factor 2 (SOX2). To investigate the role of transcriptional regulation in CP tumorigenesis, animal models were developed driven by molecular defects commonly found in CP tumors in humans. Accordingly, sustained NOTCH and Sonic Hedgehog (SHH) activation or combined deletion of Rb1 and Trp53 tumor suppressors led to malignant CP tumors with characteristics of CPC in humans. NOTCH-driven CP tumors arose from monociliated roof plate progenitors and exhibited increased levels of Lmx1a, Lmx1b, and Sox2. In contrast, their expression was significantly reduced, while OTX2 levels were markedly increased in Rb1/Trp53-deficient CPC. Consistently, single-cell transcriptomics data show a proliferative Otx2+ tumor bulk and a small Lmx1a+/Sox2+ population in Rb1/Trp53-deficient CPC. Importantly, deletion of Sox2 in Lmx1a+ progenitors blocked NOTCH-driven CP tumor and reduced Lmx1a/b expression. Thus, LMX1A and SOX2 expression marks tumor-initiating cells, while OTX2 labels differentiated tumor cells in CPC. Together, our studies revealed intra- and inter-tumoral heterogeneity in CPC driven by distinct oncogenic signals. Knowledge of the molecular and cellular basis of heterogeneity in CP tumor development may facilitate the development of innovative diagnostic and therapeutic strategies in CPC.
MDB-42. UNCOVERING DYNAMIC CHANGES IN MEDULLOBLASTOMA ASSOCIATED VASCULATURE IN ZEBRAFISH
Authors: Elysse Morris, Sheena Daignault-Mill, Robert J Ju, Jason da Silva, Emma Gordon, Brandon Wainwright, Samantha Stehbens, Laura Genovesi, Anne Lagendijk
Journal: Neuro-Oncology (2023)

Abstract Medulloblastoma (MB) is an embryonal-derived lesion arising in the cerebellum, contributing to 20% of childhood brain tumours and 63% of intracranial embryonal tumours. Currently, standard of care includes surgical resection and chemotherapy, used in conjunction with radiation. While these treatments have significantly improved survival rates, the therapy side effects are detrimental to survivors’ quality of life. Furthermore, relapse occurs in 30% of patients and unfortunately these are untreatable and therefore fatal for 95% of patients. It is presumed that in patients that present with a recurrent tumour, initial treatment has been ineffective. A major cause of this can be the heterogenous vasculature in and around the tumour. Recent studies have identified that the blood brain barrier (BBB), in the context of MB, is highly heterogenous with differences in BBB cellular composition and integrity between MB sub-types and within single tumours. It remains unclear however, how these vascular differences emerge and what the primary defects are. This gap in our knowledge is mainly due to the lack of models that allow long-term live imaging. We have established a xenograft approach to examine human MB tumour cells in zebrafish embryonal brains. We have validated that human Medulloblastoma cells of the Group 3 (Gp3) MB subgroup, are viable in zebrafish brains. This work has also identified that in the presence of these human Gp3 MB tumour cells, the local vasculature becomes dysmorphic and tortuous over time. Timelapse imaging of these tumour and vasculature interactions demonstrates that there is a rapid and long ranging angiogenic response with new vessel sprouts growing towards the tumour cells. By utilising our large range of transgenic zebrafish lines, we will continue investigating how MB cells interact and alter distinctive BBB cell types and how these changes impact vessel function.
MDB-43. GRADIENT ENTROPY-BASED RADIOMIC RISK-SCORE FROM T1-WEIGHTED PRE-TREATMENT MRI SCANS CAN PREDICT SURVIVAL IN PEDIATRIC MEDULLOBLASTOMA
Authors: Rohan Bareja, Marwa Ismail, Doug Martin, Ameya Nayate, Ipsa Yadav, Murad Labbad, Benita Tamrazi, Ralph Salloum, Ashley Margol, Alexander Judkins, Sukanya Iyer, Peter de Blank, Pallavi Tiwari
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Medulloblastoma (MB) is the most frequent malignant brain tumor in children with an inadequate 5-year survival rate of 70-75%. A key determinate in MB treatment (consisting of radiation, chemotherapy) is the accurate risk-stratification of patients into low- and high-risk. The current stratification approaches (Chang’s classification, molecular categorization) are sub-optimal in predicting individual patient outcomes. Reliable risk-assessment approaches can significantly impact treatment management. Our group previously developed a new radiomics feature COLLAGE that measures the orientation of local intensity gradients as an estimate of lesion heterogeneity. We hypothesize that the disorder (i.e., heterogeneity) in orientation of local per-voxel intensity measured by COLLAGE, will tease-out differences in patients with low - versus high-risk MB tumors. METHODS T1-weighted MRI scans of 49 pediatric MB patients were retrospectively collected from Children’s Hospital Los Angeles and Cincinnati Children’s Hospital Medical Center. Registration of the scans was performed via age-specific pediatric atlases, followed by skull stripping and bias correction. Ground truth annotations for tumor sub-compartments; enhancing tumor, edema, and non-enhancing tumor, were generated by two experienced radiologists. Then, 52 Collage features were extracted from each of these sub-compartments, followed by conducting a Lasso model and a cox-proportional hazards model to identify the top features for risk-stratification. A continuous risk score was created for every patient and a risk threshold was obtained from the fitted cox model to stratify patients into low- and high-risk. RESULTS Our risk-score consisted of 13 top COLLAGE features from edema and 14 from non-enhancing tumor sub-compartments, respectively, and demonstrated significant differences between low- and high-risk patients (p = .017 for edema, p =0.0027 for non-enhancing tumor). CONCLUSION Our preliminary analysis suggests that gradient-entropy radiomic risk score maybe able to predict overall survival in pediatric MB tumors. In future, we plan to include additional patients to perform independent multi-site analysis.
DIPG-50. INSIGHTS INTO TUMORIGENESIS OF DIFFUSE INTRINSIC PONTINE GLIOMA-ONCOHISTONE AND SIGNALING
Authors: Ye Sun, Kun Yan, Dan Wang, Wei Zhou, Yi Wang, Cheng Xu, Yujie Han, Yujie Tang, Liwei Zhang, Qiaoran Xi
Journal: Neuro-Oncology (2023)

Abstract Diffuse intrinsic pontine glioma (DIPG) is a rare and incurable pediatric brain cancer with survival of less than one year. Understanding the tumorigenesis mechanisms of DIPG and identifying potential therapeutic strategy are major research foci in the DIPG field. The most lethal subtype of diffuse intrinsic pontine glioma (DIPG) is the H3K27M subtype. Although ACVR1 mutations have been implicated in the pathogenesis of this presently incurable disease, the impacts of BMP signaling on more than 60% of H3K27M DIPG carrying ACVR1 wild-type remain unknown. Here, we show that BMP ligands exert potent tumor suppressive effects against H3.3 K27M and ACVR1 WT DIPG in a SMAD-dependent manner. Specifically, clinical data revealed that many DIPG tumors have exploited CHRDL1’s capacity to hijack BMP ligands. We discovered activation of BMP signaling promotes the exit of DIPG tumor cells from “prolonged-stem-cell-like” state to differentiation by epigenetically regulating CXXC5, which acts as a tumor suppressor and positive regulator of BMP signaling. Beyond showing how BMP signaling impacts DIPG, our study also identified potent anti-tumor efficacy of Dacinostat for DIPG. Thus, our study delineates context-dependent features of BMP signaling pathway in DIPG subtype.
OUTC-11. RACE AND AGE ARE ASSOCIATED WITH ICD-10 DIAGNOSES IN THE POST-OPERATIVE PERIOD FOR PEDIATRIC PATIENTS WITH PRIMARY BRAIN TUMORS UNDERGOING NEUROSURGERY
Authors: Canada Montgomery, Alexa Plisiewicz, Chao Zhao, Ying Yan, Charles Phillips, Kaitlin Lehmann, Phillip Storm, Peter Madsen, Cassie Kline
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Disparities in pediatric cancer care and outcomes are known to exist. This work evaluates the relationship of race, ethnicity, and social determinants of health (SDoH) on the post-operative neurosurgical course of pediatric neuro-oncology patients in a single-institution. METHODS Retrospective data were collected on patients undergoing initial neurosurgery for a primary central nervous system (CNS) tumor between May 2011 and April 2021. Newly attributed ICD-10 codes in the 30-day post-operative period were collected. Descriptive statistics were used to evaluate demographics, geographic region of residence, and insurance type. Logistic regression was performed to estimate the association between covariates and 30-day readmission as well as ICD-10 diagnoses that can complicate the postoperative course including cardiac/respiratory, bleeding, infection, wound, hardware implantation, and neurologic conditions. Linear regression was used to measure association of covariates and length of stay (LOS). RESULTS A total of 836 patients, median age 10.0 years, were included (n=368 females, 44%). Patients were predominantly white (69%) and non-Hispanic/Latino (88%). White (OR [95% CI] 0.55 [0.33,0.90], p=0.02), Native American/Indian (0.25 [0.07,0.89], p=0.03), and multiracial (0.24 [0.08,0.68], p=0.01) patients were significantly less likely to have new ICD-10 codes compared to Black patients. White patients trended toward shorter LOS (p=0.06) compared to Black patients. Younger patients were significantly more likely to have newly reported ICD-10 codes (0.95 [0.92,0.97], p&amp;lt;0.001), increased LOS (r=-0.59 [-0.87,-0.32], p&amp;lt;0.001), and 30-day readmission (0.81 [0.72,0.89], p&amp;lt;0.001). Sex, ethnicity, insurance type, and region had no significant association with outcomes. Income level analyses are ongoing. CONCLUSION Non-black patients were less likely to have new ICD-10 diagnoses reported after surgery for primary CNS tumors. Older age was a protective factor against new post-operative diagnoses, increased LOS, and mortality. More research is necessary to understand the relationship between race, ethnicity, SDoH and post-operative risk including possible mechanisms of interaction across variables.
CNSC-02. INVESTIGATING THE ROLE OF THE WNT SIGNALING TRANSDUCTION PATHWAY IN GLIOMA BLOOD-BRAIN-BARRIER INTEGRITY
Authors: Kayen Tang, Christina Conrad, Sanghee Lim, Minhye Kwak, Melissa Cesaire, Sadhana Jackson
Journal: Neuro-Oncology (2023)

Abstract The WNT signaling transduction pathway has been linked to cancer stem cell self-renewal, differentiation, and blood brain barrier (BBB) development. Previous studies have shown that WNT pathway inhibition increased BBB permeability, specifically in WNT medulloblastoma. Glioblastoma, an aggressive malignant tumor with poor prognosis, has also been shown to have high WNT expression and variable BBB permeability. We hypothesize that activating WNT pathway inhibition in glioblastoma stem cells (GSCs) will inhibit glioma progression, increase BBB permeability within the tumor microenvironment, and enhance overall treatment responsiveness. We transduced primary pediatric derived glioma stem cells with overexpressing vectors for WNT inhibitors (DKK1 or WIF1). To characterize effects of DKK1 or WIF1 overexpression, we evaluated cell migration patterns via RTCA xCelligence, cell cycle progression via Annexin 5 assays, and cell viability via cell-titer glo. Brain endothelial cell integrity was evaluated with the treatment of CHIR99021, WNT pathway activator, or GSC condition media with immunoblotting for junctional protein expression (Claudin-5, Claudin-3, Occludin, ZO-1, VE-Cadherin). Verification of WNT inhibitory overexpressing GSCs for DKK1 and WIF1 was performed using RNAseq, proteomics, and immunoblotting. DKK1-GSCs demonstrated a statistically significant impairment in the migratory slope compared to empty vector GSCs. Cell cycle analysis also revealed that DKK1-GSCs were arrested in G0/1 phase while WIF1-GSCs were arrested in S/G2M phase. CHIR99021 endothelial treatment resulted in increased secretion of WNT inhibitors DKK1 and SFRP1 and resultantly, there was a decrease in junctional protein expression. Overall, WNT inhibitor overexpressing GSCs exhibited unique cellular patterns and indirectly disrupted endothelial cell integrity. Future studies will evaluate orthotopic WNT inhibitor overexpressing transplant rodent models to determine BBB integrity, drug permeability, model survival, and chemotherapeutic treatment response. By enhancing our understanding of the WNT pathway in GSCs, we anticipate understanding the use of future therapeutic WNT pathway targeting to increase chemotherapeutic responsiveness and improve glioblastoma prognosis.
HGG-13. ONCOGENIC STAT3 AND SHP2 ACTIVATION IN ROS1-FUSION DRIVEN INFANT-TYPE HEMISPHERIC GLIOMAS
Authors: Andreas Postlmayr, Andrea De Micheli, Nina Hofmann, Marc Zuckermann, Ana Guerreiro Stücklin
Journal: Neuro-Oncology (2023)

Abstract Genomic analyzes identified a subgroup of gliomas – infant-type hemispheric gliomas – that are driven by oncogenic fusions of, amongst others, ROS1 receptor tyrosine kinase with a variety of fusion partners. These fusions result in ligand independent constitutively active oncogenic kinases. In the present study we aim to identify the, yet poorly characterized, alterations in cellular signaling driven by ROS1 fusions leading to tumor formation to enhance our understanding of IHG formation and to identify complementary targets for therapy. To answer these questions, we deploy a combination of biochemical characterization of cellular models as well as in vivo experiments and transcriptomic and phosphoproteomic analyzes. Expression of different ROS1-fusions results in robust tumor formation in two different mouse models, proving their tumorigenic potential. The impact of the fusion partner, which dictates subcellular localization, as shown by immunofluorescence microscopy, on differences in tumor formation has not yet been established. Transcriptomic and phosphoproteomic analyses of ROS1-fusion cellular models revealed diverging effects of the fusions on transcriptomic and proteomic alterations. A common denominator, however, is a significant hyper-phosphorylation of the tyrosine phosphatase SHP2, which we established to be a direct substrate of ROS1. ROS1 fusions, irrespective of the fusion partner, drive non-canonical STAT3 signaling, indicated by direct phosphorylation of STAT3 by ROS1 and upregulation of STAT3 target genes. Characterizing the main signaling pathways using immunoblots did not detect alterations in the PI3K/AKT/mTOR or MAPK pathways. STAT3 signaling is a well characterized pathway for promoting pro-survival, proliferation and stemness cues in development and cancer, making it a paramount candidate for ROS1 driven tumorigenesis as well as an excellent target for targeted therapies.